Pharmaceutical formulation

Abstract

Stable pharmaceutical compositions useful for administering methylnaltrexone are described, as are methods for making the same. Kits, including these pharmaceutical compositions, also are provided.

We claim:  
     
         1 . A pharmaceutical preparation comprising a solution of methylnaltrexone or a salt thereof, wherein the preparation after autoclaving has a concentration of methylnaltrexone degradation products that does not exceed 2% of the methylnaltrexone or salt thereof in the preparation.  
     
     
         2 - 6 . (canceled)  
     
     
         7 . The pharmaceutical preparation of  claim 1 , wherein the pharmaceutical preparation further comprises a chelating agent.  
     
     
         8 . The pharmaceutical preparation of  claim 7 , wherein the chelating agent is ethylenediaminetetraacetic acid (EDTA) or a derivative thereof.  
     
     
         9 . (canceled)  
     
     
         10 . The pharmaceutical preparation of  claim 8 , wherein the EDTA or derivative thereof is present in a concentration ranging from 0.001 to 100.0 mg/ml.  
     
     
         11 - 16 . (canceled)  
     
     
         17 . The pharmaceutical preparation of  claim 1 , further comprising a buffering agent.  
     
     
         18 . The pharmaceutical preparation of  claim 17 , wherein the buffering agent is citrate buffer.  
     
     
         19 . The pharmaceutical preparation of  claim 18 , wherein the citrate is present in a concentration ranging from 0.01 to 100.0 mM.  
     
     
         20 - 21 . (canceled)  
     
     
         22 . The pharmaceutical preparation of  claim 1 , wherein the pH of the preparation does not exceed 4.25.  
     
     
         23 - 25 . (canceled)  
     
     
         26 . The pharmaceutical preparation of  claim 1 , wherein the concentration of methylnaltrexone ranges from 0.01 to 100 mg/ml.  
     
     
         27 - 32 . (canceled)  
     
     
         33 . The pharmaceutical preparation of  claim 1 , further comprising an anti-oxidant.  
     
     
         34 . The pharmaceutical preparation of  claim 1 , further comprising an isotonicity agent.  
     
     
         35 . The pharmaceutical preparation of  claim 1 , further comprising an opioid.  
     
     
         36 . The pharmaceutical preparation of  claim 1 , further comprising a cryoprotective agent.  
     
     
         37 . The pharmaceutical preparation of  claim 36 , wherein the cryoprotective agent is a polyol.  
     
     
         38 . The pharmaceutical preparation of  claim 1 , wherein the solution is provided in a vial or ampoule with a septum.  
     
     
         39 . The pharmaceutical preparation of  claim 1 , wherein the solution is provided in a syringe, infusion bag or sealable bottle.  
     
     
         40 - 43 . (canceled)  
     
     
         44 . The pharmaceutical preparation of  claim 1 , wherein the solution is provided in a container including indicia indicating that the pharmaceutical preparation has been autoclaved.  
     
     
         45 - 49 . (canceled)  
     
     
         50 . A method for preparing an autoclaved pharmaceutical preparation that has a concentration of methylnaltrexone degradation products that does not exceed 2% of the methylnaltrexone or salt thereof in the preparation comprising: 
 providing a solution having a pH of 4.25 or less comprising methylnaltrexone or salt thereof and being substantially free of methylnaltrexone degradation products; and    autoclaving the solution.    
     
     
         51 - 53 . (canceled)  
     
     
         54 . The method of  claim 50 , wherein the solution contains a chelating agent.  
     
     
         55 . The method of  claim 50 , wherein the solution further comprises an isotonicity agent.  
     
     
         56 . The method of  claim 50 , wherein the solution comprises a buffering agent.  
     
     
         57 . (canceled)  
     
     
         58 . The method of  claim 50 , wherein the solution comprises an anti-oxidant.  
     
     
         59 - 60 . (canceled)  
     
     
         61 . The method of  claim 54 , wherein the chelating agent is EDTA or derivative thereof.  
     
     
         62 . The method of  claim 56 , wherein the buffering agent is citrate buffer.  
     
     
         63 . The method of  claim 50 , further comprising lyophilizing the solution.  
     
     
         64 . The method of  claim 63 , further comprising adding a cryoprotecting agent to the solution.  
     
     
         65 . The method of  claim 63 , wherein the cryoprotective agent is a polyol.  
     
     
         66 . A method for preparing an autoclaved pharmaceutical preparation that has a concentration of methylnaltrexone degradation products that does not exceed 2% of the methylnaltrexone or salt thereof in the preparation comprising: 
 providing a solution comprising methylnaltrexone or salt thereof and a chelating agent, the solution being substantially free of methylnaltrexone degradation products; and    autoclaving the solution.    
     
     
         67 . The method of  claim 66 , wherein the chelating agent is EDTA or derivative thereof.  
     
     
         68 . The method of  claim 67 , wherein the EDTA or derivative thereof is present in a concentration ranging from 0.001 to 100.0 mg/ml.  
     
     
         69 - 70 . (canceled)  
     
     
         71 . The method of  claim 66 , wherein the solution contains a buffering agent.  
     
     
         72 . The method of  claim 71 , wherein the buffering agent is citrate buffer.  
     
     
         73 . The method of  claim 66 , wherein the solution is adjusted to have a pH of 4.25 or less.  
     
     
         74 - 76 . (canceled)  
     
     
         77 . The method of  claim 66 , wherein the solution contains an anti-oxidant.  
     
     
         78 . The method of  claim 66 , wherein the solution contains an isotonicity agent.  
     
     
         79 - 82 . (canceled)  
     
     
         83 . The method of  claim 66 , further comprising lyophilizing the solution.  
     
     
         84 . The method of  claim 83 , further comprising adding a cryoprotecting agent to the solution.  
     
     
         85 . The method of  claim 84 , wherein the cryoprotective agent is a polyol.  
     
     
         86 . A pharmaceutical preparation comprising a solution of methylnaltrexone or a salt thereof, wherein the preparation after storage at about room temperature for six months has a concentration of methylnaltrexone degradation products that does not exceed 2% of the methylnaltrexone in the preparation.  
     
     
         87 - 91 . (canceled)  
     
     
         92 . The pharmaceutical preparation of  claim 86 , wherein the pharmaceutical preparation further comprises a chelating agent.  
     
     
         93 . The pharmaceutical preparation of  claim 92 , wherein the chelating agent is EDTA or derivative thereof.  
     
     
         94 . The pharmaceutical preparation of  claim 93 , wherein the EDTA or derivative thereof is present in a concentration ranging from 0.001 to 100.0 mg/ml.  
     
     
         95 - 100 . (canceled)  
     
     
         101 . The pharmaceutical preparation of  claim 86 , wherein the pharmaceutical preparation further comprises a buffering agent.  
     
     
         102 . The pharmaceutical preparation of  claim 86 , wherein the buffering agent is citrate buffer.  
     
     
         103 . The pharmaceutical preparation of  claim 102 , wherein the citrate is present in a concentration ranging from 0.01 to 100.0 mM.  
     
     
         104 - 105 . (canceled)  
     
     
         106 . The pharmaceutical preparation of  claim 86 , wherein the pH does not exceed 4.25.  
     
     
         107 - 109 . (canceled)  
     
     
         110 . The pharmaceutical preparation of  claim 86 , wherein the concentration of methylnaltrexone ranges from 0.01 to 100 mg/ml.  
     
     
         111 - 116 . (canceled)  
     
     
         117 . The pharmaceutical preparation of  claim 86 , further comprising an anti-oxidant.  
     
     
         118 . The pharmaceutical preparation of  claim 86 , further comprising an isotonicity agent.  
     
     
         119 . The pharmaceutical preparation  claim 86 , further comprising a cryoprotective agent.  
     
     
         120 . The pharmaceutical preparation of  claim 119 , wherein the cryoprotective agent is a polyol.  
     
     
         121 . The pharmaceutical preparation of  claim 86 , further comprising an opioid.  
     
     
         122 - 128 . (canceled)  
     
     
         129 . The pharmaceutical preparation of  claim 86 , wherein the solution is provided in a vial or ampoule with a septum, in a syringe, an infusion bag, or a sealable bottle.  
     
     
         130 - 132 . (canceled)  
     
     
         133 . The pharmaceutical preparation of  claim 86 , wherein the solution is provided in a container including indicia indicating that the solution has been autoclaved.  
     
     
         134 - 135 . (canceled)  
     
     
         136 . A stable pharmaceutical preparation comprising a solution of methylnaltrexone or salt thereof, wherein the pH is below 4.25.  
     
     
         137 - 139 . (canceled)  
     
     
         140 . The pharmaceutical preparation of  claim 136 , wherein the pH is adjusted with an acid selected from the group consisting of HCI, citric acid, sulfuric acid, acetic acid, or phosphoric acid.  
     
     
         141 . The pharmaceutical preparation of  claim 136 , wherein the preparation further comprises a buffering agent.  
     
     
         142 . The pharmaceutical preparation of  claim 141 , wherein the buffering agent is selected from the group consisting of citric acid, sodium citrate, sodium acetate, acetic acid, sodium phosphate and phosphoric acid, sodium ascorbate, tartartic acid, maleic acid, glycine, sodium lactate, lactic acid, ascorbic acid, imidazole, sodium bicarbonate and carbonic acid, sodium succinate and succinic acid, histidine, and sodium benzoate and benzoic acid.  
     
     
         143 . The pharmaceutical preparation of  claim 141 , wherein the buffering agent is a citrate buffer.  
     
     
         144 . The pharmaceutical preparation of  claim 143 , wherein the citrate buffer concentration ranges from 0.001 mM to 100 mM.  
     
     
         145 - 146 . (canceled)  
     
     
         147 . The pharmaceutical preparation of  claim 136 , further comprising a chelating agent.  
     
     
         148 . (canceled)  
     
     
         149 . The pharmaceutical preparation of  claim 147 , wherein the chelating agent is selected from the group consisting of EDTA and derivatives thereof, citric acid and derivatives thereof, niacinamide and derivatives sodium desoxycholate and derivatives thereof.  
     
     
         150 - 154 . (canceled)  
     
     
         155 . The pharmaceutical preparation of  claim 136 , wherein the preparation is substantially free of methylnaltrexone degradation products.  
     
     
         156 - 157 . (canceled)  
     
     
         158 . The pharmaceutical preparation of  claim 136 , wherein the pharmaceutical preparation has been autoclaved and the concentration of methylnaltrexone degradation products is less than 2.0% of the methylnaltrexone in the preparation.  
     
     
         159 - 162 . (canceled)  
     
     
         163 . The pharmaceutical preparation of  claim 136 , wherein the methylnaltrexone or salt thereof is present in an amount effective to treat a side effect associated with opioid treatment when administered to a human subject.  
     
     
         164 . The pharmaceutical preparation of  claim 163 , wherein the concentration of methylnaltrexone or salt thereof is sufficient to treat constipation.  
     
     
         165 . The pharmaceutical preparation of  claim 136 , wherein the concentration of methylnaltrexone or salt thereof ranges from 0.01 to 100 mg/ml.  
     
     
         166 - 171 . (canceled)  
     
     
         172 . The pharmaceutical composition of  claim 141 , further comprising an isotonicity agent.  
     
     
         173 - 175 . (canceled)  
     
     
         176 . The preparation of  claim 136 , further comprising an antioxidant.  
     
     
         177 - 178 . (canceled)  
     
     
         179 . The preparation of  claim 176 , wherein the antioxidant is selected from the group consisting of an ascorbic acid derivative, butylated hydroxy anisole, butylated hydroxy toluene, alkyl gallate, sodium meta-bisulfite, sodium bisulfite, sodium dithionite, sodium thioglycollic acid, sodium formaldehyde sulfoxylate, tocopherol and derivatives thereof, monothioglycerol, and sodium sulfite.  
     
     
         180 . The preparation of  claim 136 , further comprising a cryoprotective agent.  
     
     
         181 - 182 . (canceled)  
     
     
         183 . The preparation of  claim 180  wherein the cryoprotective agent is a polyol.  
     
     
         184 . The preparation of  claim 136 , further comprising an opioid.  
     
     
         185 - 186 . (canceled)  
     
     
         187 . The preparation of  claim 184 , wherein the opioid is selected from the group consisting of alfentanil, anileridine, asimadoline, bremazocine, burprenorphine, butorphanol, codeine, dezocine, diacetylmorphine (heroin), dihydrocodeine, diphenoxylate, fedotozine, fentanyl, funaltrexamine, hydrocodone, hydromorphone, levallorphan, levomethadyl acetate, levorphanol, loperamide, meperidine (pethidine), methadone, morphine, morphine-6-glucoronide, nalbuphine, nalorphine, opium, oxycodone, oxymorphone, pentazocine, propiram, propoxyphene, remifentanyl, sufentanil, tilidine, trimebutine, and tramadol.  
     
     
         188 . A stable pharmaceutical preparation comprising a solution of methylnaltrexone or salt thereof, wherein the solution further comprises a chelating agent in an amount sufficient to inhibit degradation of the methylnaltrexone or salt thereof, whereby the amount is such that the preparation after autoclaving has a concentration of methylnaltrexone degradation products that does not exceed 0.5% of the methylnaltrexone or salt thereof in the preparation.  
     
     
         189 . The pharmaceutical preparation of  claim 188 , wherein the chelating agent is selected from the group consisting of EDTA and derivatives thereof, citric acid and derivatives thereof, niacinamide and derivatives thereof, and sodium desoxycholate and derivatives thereof.  
     
     
         190 - 194 . (canceled)  
     
     
         195 . The pharmaceutical preparation of  claim 188 , wherein the preparation further comprises a buffering agent.  
     
     
         196 . The pharmaceutical preparation of  claim 195 , wherein the buffering agent is selected from the group consisting of citric acid, sodium citrate, sodium acetate, acetic acid, sodium phosphate and phosphoric acid, sodium ascorbate, tartartic acid, maleic acid, glycine, sodium lactate, lactic acid, ascorbic acid, imidazole, sodium bicarbonate and carbonic acid, sodium succinate and succinic acid, histidine, and sodium benzoate and benzoic acid.  
     
     
         197 - 201 . (canceled)  
     
     
         202 . The pharmaceutical preparation of  claim 188 , wherein the preparation is substantially free of methylnaltrexone degradation products.  
     
     
         203 - 205 . (canceled)  
     
     
         206 . The pharmaceutical preparation of  claim 188 , wherein the methylnaltrexone or salt thereof is present in an amount effective to treat a side effect associated with opioid treatment when administered to a human subject.  
     
     
         207 . The pharmaceutical preparation of  claim 206 , wherein the concentration of methylnaltrexone or salt thereof is sufficient to treat constipation.  
     
     
         208 . The pharmaceutical preparation of  claim 188 , wherein the concentration of methylnaltrexone or salt thereof ranges from 0.01 to 100 mg/ml.  
     
     
         209 - 213 . (canceled)  
     
     
         214 . The pharmaceutical composition of  claim 188 , further comprising an isotonicity agent.  
     
     
         215 . (canceled)  
     
     
         216 . The composition of  claim 214 , wherein the isotonicity agent is selected from the group consisting of sodium chloride, mannitol, lactose, dextrose, glycerol, and sorbitol.  
     
     
         217 . (canceled)  
     
     
         218 . (canceled)  
     
     
         219 . The preparation of  claim 188 , further comprising an antioxidant.  
     
     
         220 . (canceled)  
     
     
         221 . The preparation of  claim 219 , wherein the antioxidant is selected from the group consisting of an ascorbic acid derivative, butylated hydroxy anisole, butylated hydroxy toluene, alkyl gallate, sodium meta-bisulfite, sodium bisulfite, sodium dithionite, sodium thioglycollic acid, sodium formaldehyde sulfoxylate, tocopherol and derivatives thereof, monothioglycerol, and sodium sulfite.  
     
     
         222 . (canceled)  
     
     
         223 . The preparation of  claim 188 , further comprising a cryoprotective agent.  
     
     
         224 . (canceled)  
     
     
         225 . The preparation of  claim 188 , further comprising an opioid.  
     
     
         226 . (canceled)  
     
     
         227 . (canceled)  
     
     
         228 . The preparation of  claim 225 , wherein the opioid is selected from the group consisting of alfentanil, anileridine, asimadoline, bremazocine, burprenorphine, butorphanol, codeine, dezocine, diacetylmorphine (heroin), dihydrocodeine, diphenoxylate, fedotozine, fentanyl, funaltrexamine, hydrocodone, hydromorphone, levallorphan, levomethadyl acetate, levorphanol, loperamide, meperidine (pethidine), methadone, morphine, morphine-6-glucoronide, nalbuphine, nalorphine, opium, oxycodone, oxymorphone, pentazocine, propiram, propoxyphene, remifentanyl, sufentanil, tilidine, trimebutine, and tramadol.  
     
     
         29 . (canceled)  
     
     
         230 . (canceled)  
     
     
         231 . A pharmaceutical preparation comprising a solution of methylnaltrexone or salt thereof and at least one methylnaltrexone degradation inhibiting agent selected from the group consisting of a chelating agent, a buffering agent, an antioxidant, and combinations thereof, wherein the solution has a pH ranging from 2 to 6, wherein the degradation inhibiting agent is present in an amount sufficient to render the preparation stable, wherein the preparation is processed under at least one sterilization technique, and wherein the preparation is substantially free of methylnaltrexone degradation products.  
     
     
         232 . The pharmaceutical preparation of  claim 231 , wherein the preparation is stable to storage for 6 months at about room temperature.  
     
     
         233 . (canceled)  
     
     
         234 . (canceled)  
     
     
         235 . The pharmaceutical preparation of  claim 231 , wherein the preparation is stable to autoclaving.  
     
     
         236 . The pharmaceutical preparation of  claim 231 , further comprising an isotonicity agent.  
     
     
         237 . The preparation of  claim 231 , further comprising a cryoprotective agent.  
     
     
         238 . The pharmaceutical preparation of  claim 231 , further comprising an opioid.  
     
     
         239 . The pharmaceutical preparation of  claim 238 , wherein the opioid is selected from the group consisting of alfentanil, anileridine, asimadoline, bremazocine, burprenorphine, butorphanol, codeine, dezocine, diacetylmorphine (heroin), dihydrocodeine, diphenoxylate, fedotozine, fentanyl, funaltrexamine, hydrocodone, hydromorphone, levallorphan, levomethadyl acetate, levorphanol, loperamide, meperidine (pethidine), methadone, morphine, morphine-6-glucoronide, nalbuphine, nalorphine, opium, oxycodone, oxymorphone, pentazocine, propiram, propoxyphene, remifentanyl, sufentanil, tilidine, trimebutine, and tramadol.  
     
     
         240 . The pharmaceutical preparation of  claim 231 , wherein the preparation is provided in a vial or an ampoule with a septum.  
     
     
         241 . The pharmaceutical preparation of  claim 231 , wherein the preparation is provided in an infusion bag.  
     
     
         242 . The pharmaceutical preparation of  claim 231 , wherein the preparation is provided in a syringe.  
     
     
         243 . The pharmaceutical preparation of  claim 231 , wherein the preparation is provided in a sealable bottle.  
     
     
         244 . The pharmaceutical preparation of  claim 231 , wherein the preparation is suitable for parenteral administration.  
     
     
         245 . The pharmaceutical preparation of  claim 231 , wherein the preparation is suitable for oral imbibing.  
     
     
         246 . The pharmaceutical preparation of  claim 231 , wherein the solution is provided in a container including indicia indicating the preparation has been processed under at least one sterilization technique.  
     
     
         247 . A method of inhibiting formation of methylnaltrexone degradation products in a pharmaceutical preparation comprising methylnaltrexone or salts thereof, the method comprising: 
 preparing an aqueous solution comprising at least one methylnaltrexone degradation inhibiting agent selected from the group consisting of a chelating agent, a buffering agent, an antioxidant, and combinations thereof, dissolving a powdered source of methylnaltrexone or salt thereof with the solution to form the pharmaceutical preparation.    
     
     
         248 - 251 . (canceled)  
     
     
         252 . The method of  claim 247 , further comprising adjusting with an acid the pH of the solution or the preparation to a pH ranging from 2 to 6.  
     
     
         253 . (canceled)  
     
     
         254 . (canceled)  
     
     
         255 . The method of  claim 247 , further comprising adding an isotonicity agent to the solution.  
     
     
         256 . A method of preparing a stable pharmaceutical preparation comprising an aqueous solution of methylnaltrexone or salts thereof to inhibit formation of methylnaltrexone degradation products, comprising: 
 providing a solution comprising methylnaltrexone or salts thereof and at least one methylnaltrexone degradation inhibiting agent;    processing the solution under at least one sterilization technique prior to and/or after terminal filling the solution in a sealable container to form the stable pharmaceutical preparation, wherein the method is carried out without the addition of a pH-adjusting-base to the solution.    
     
     
         257 . The method according to  claim 256 , wherein the concentration of methylnaltrexone degradation products is less than 2.0% of the total methylnaltrexone in the preparation.  
     
     
         258 - 260 . (canceled)  
     
     
         261 . The method of  claim 256 , wherein the methylnaltrexone degradation inhibiting agent is selected from the group consisting of a chelating agent, a buffering agent, an antioxidant, and combinations thereof.  
     
     
         262 - 266 . (canceled)  
     
     
         267 . The method of  claim 256 , wherein the initial solution is adjusted to a pH ranging from 2 to 6 prior to the processing under the at least one sterilization technique.  
     
     
         268 - 270 . (canceled)  
     
     
         271 . The method of  claim 256 , wherein the aseptic technique is autoclaving after terminal filling the sealable container.  
     
     
         272 . The method of  claim 256 , wherein the processing comprises sterile filtration prior to terminal filling followed by autoclaving after terminal filling the sealable container.  
     
     
         273 . The method of  claim 256 , further comprising sealing the container, wherein the container is purged with nitrogen.  
     
     
         274 . The method of  claim 256 , further comprising sealing the container, wherein the container is sparged to eliminate oxygen.  
     
     
         275 . The method of  claim 256 , wherein the initial solution further comprises an isotonicity agent.  
     
     
         276 . The method of  claim 275 , wherein the isotonicity agent is sodium chloride.  
     
     
         277 . The method of  claim 256 , wherein the initial solution further comprising a cryoprotective agent.  
     
     
         278 . The method of  claim 277  wherein the cryoprotective agent is a polyol.  
     
     
         279 . The method of  claim 256 , further comprising adding at least one opioid to the initial solution.  
     
     
         280 . The method of  claim 279 , wherein the opioid is selected from the group consisting of alfentanil, anileridine, asimadoline, bremazocine, burprenorphine, butorphanol, codeine, dezocine, diacetylmorphine (heroin), dihydrocodeine, diphenoxylate, fedotozine, fentanyl, funaltrexamine, hydrocodone, hydromorphone, levallorphan, levomethadyl acetate, levorphanol, loperamide, meperidine (pethidine), methadone, morphine, morphine-6-glucoronide, nalbuphine, nalorphine, opium, oxycodone, oxymorphone, pentazocine, propiram, propoxyphene, remifentanyl, sufentanil, tilidine, trimebutine, and tramadol.  
     
     
         281 . The method of  claim 279 , wherein the opioid is solubilized in a nonaqueous solvent prior to addition to the initial solution.  
     
     
         282 . The method of  claim 281 , wherein the nonaqueous solvent is an oil, wax, or alcohol.  
     
     
         283 . A product comprising 
 a stable lyophilized formulation of methylnaltrexone, wherein the formulation upon reconstitution in water at a concentration of 20 mg/ml has a pH of between 2 and 6.    
     
     
         284 . (canceled)  
     
     
         285 . The product of  claim 283 , wherein the formulation comprises a cryoprotecting agent present in an amount sufficient to render the formulation stable.  
     
     
         286 . (canceled)  
     
     
         287 . The product of  claim 285 , wherein the cryoprotecting agent is a polyol.  
     
     
         288 . (canceled)  
     
     
         289 . The product of  claim 285 , wherein the cryoprotecting agent is mannitol.  
     
     
         290 . (canceled)  
     
     
         291 . The product of  claim 283 , further comprising any one or more of a buffering agent, a chelating agent and an antioxidant.  
     
     
         292 . (canceled)  
     
     
         293 . A product comprising 
 a lyophilized formulation of methylnaltrexone prepared from a solution comprising the solution of  claim 1 .    
     
     
         294 . A product comprising 
 a lyophilized formulation of methylnaltrexone prepared from a solution comprising the solution of  claim 36 .    
     
     
         295 . (canceled)  
     
     
         296 . A product comprising 
 a lyophilized formulation of methylnaltrexone prepared from a solution comprising the solution of claims  claim 86 .    
     
     
         297 . (canceled)  
     
     
         298 . (canceled)  
     
     
         299 . A product comprising 
 a lyophilized formulation of methylnaltrexone prepared from a solution comprising the solution of  claim 136 .    
     
     
         300 . (canceled)  
     
     
         301 . (canceled)  
     
     
         302 . A product comprising 
 methylnaltrexone and a degradation inhibiting agent selected from the group consisting of a chelating agent, a buffering agent, an anti-oxidant, and combinations thereof, wherein the degradation inhibiting agent is present in an amount sufficient to render stable a solution of the product containing a concentration of 20 mg/ml methylnaltrexone.    
     
     
         303 . The product of  claim 302 , wherein the product when in solution at a concentration of 20 mg/ml methylnaltrexone yields a solution with a pH of between 2 and 6.  
     
     
         304 . The product of  claim 303 , wherein the product has less than 1% methylnaltrexone degradation products when stored at room temperature in the solution for 6 months.  
     
     
         305 . (canceled)  
     
     
         306 . (canceled)  
     
     
         307 . A pharmaceutical preparation comprising methylnaltrexone; 
 sodium chloride,    citric acid,    trisodium citrate, and    disodium edetate.    
     
     
         308 . The pharmaceutical preparation of  claim 307 , wherein the preparation is a solution and the methylnaltrexone is present at between 20 and 40 mg/ml, the sodium chloride is present between 2 and 6 mg/ml, the citric acid is present between 0.05 and 0.1 mg/ml, the trisodium citrate is present between 0.025 and 0.075 mg/ml and the disodium edetate is present between 0.5 and 1.0 mg/ml.  
     
     
         309 . A kit comprising a package containing a sealed container comprising the pharmaceutical preparation of  claim 231 , and instructions for use.  
     
     
         310 . The kit of  claim 309 , further comprising a diluant container containing a pharmaceutically acceptable diluant.  
     
     
         311 . The kit of  claim 310 , further comprising instructions for mixing the preparation and diluant.  
     
     
         312 . The kit of  claim 310 , wherein the diluant is selected from the group consisting of a 5% dextrose solution and a physiological saline solution.  
     
     
         313 . The kit of  claim 310 , wherein the diluant is contained in a sealable bottle or an infusion bag.  
     
     
         314 . The kit of  claim 309 , further comprising an opioid container containing an opioid.  
     
     
         315 . The kit of  claim 314 , wherein the opioid is selected from the group consisting of alfentanil, anileridine, asimadoline, bremazocine, burprenorphine, butorphanol, codeine, dezocine, diacetylmorphine (heroin), dihydrocodeine, diphenoxylate, fedotozine, fentanyl, funaltrexamine, hydrocodone, hydromorphone, levallorphan, levomethadyl acetate, levorphanol, loperamide, meperidine (pethidine), methadone, morphine, morphine-6-glucoronide, nalbuphine, nalorphine, opium, oxycodone, oxymorphone, pentazocine, propiram, propoxyphene, remifentanyl, sufentanil, tilidine, trimebutine, and tramadol.